Kids Kidney Research

Membranoproliferative glomerulonephritis (MPGN) is the term given to a group of rare, progressive kidney disorders. The diagnosis is made by looking at a kidney biopsy, which shows characteristic patterns of inflammation and damage seen in glomeruli. Glomeruli are highly specialised blood vessels. They are the microscopic filters of the kidney where waste products are cleared from the bloodstream.

MPGN can be divided into subtypes based upon the kidney biopsy findings. MPGN type 1 and 3 share similarities, but MPGN type 2 is distinctive in its pure form and is known as Dense Deposit Disease (DDD). Most patients lose large amounts of protein +/- blood in their urine and so become swollen (nephrotic syndrome). Broadly speaking MPGN is untreatable, and most patients lose kidney function over about a decade, and they become dependent upon dialysis. In some cases the disease recurs in a transplant.

The cause is unknown in detail, but complement regulation is usually abnormal. Complement is the term given to a cascade of interacting proteins that form part of the immune response. Complement is deposited in glomeruli and is likely to be important in the disease process. Antibodies are immune proteins in the bloodstream which usually attack germs. Antibodies that react against complement are found in some patients and can activate complement when tested in the laboratory. Rarely, patients have been described with inherited defects of complement regulatory proteins such as Factor H. Mice with no Factor H (Factor H knock-out) develop MPGN, and this is a model of the disease. Together this suggests that abnormal complement activity could be at the centre of the problem.

Because of its rarity MPGN is difficult to study. The National Registry of Rare Kidney Disease (eponym RaDaR) is recruiting patients with MPGN of all subtypes from the whole UK population starting with children. 80 cases will be analysed over 2 years. The intention is to identify well characterised cohorts (groups) of patients in sufficient numbers to conduct clinical trials with novel agents, particularly those that

block complement activation. In order to reach this target, the traditional way we diagnose MPGN on kidney biopsy needs to be reconsidered, and both conventional and novel biomarkers (things we can measure in a patient to tell us about their disease without having to obtain repeated kidney biopsies) need to be developed and applied.

Biomarkers are particularly useful if they can tell us more about the disease process. The research group will pay specific attention to changes in complement proteins that signal complement activation, the levels of complement regulatory proteins, and the presence of anti-complement antibodies, Abnormalities in the genes encoding complement regulatory proteins will be sought (gene mutations). The way these mutations

relate to disease findings in the patient will be assessed (Genotype-phenotype correlation). Special forms of statistical analysis will be undertaken to ensure meaningful results.

The project is multi-centre, drawing together the expertise of a panel of research pathologists, complement protein scientists, immunologists, geneticists and clinicians. It is part funded by MRC and KRUK. This application is necessary to enable specimen collection and distribution, kidney biopsy re-examination and provide coordination and governance of these essential parts of the project.